Project Summary/Abstract Although the WTC general responders cohort is aging (average age=56), the WTC Health Program (WTCHP) does not routinely collect data on aging-related syndromes. In particular, frailty is a syndrome characterized by increased vulnerability to adverse events including mortality, morbidity, disability, and hospitalizations. Our preliminary data indicate that almost one-third of the General Responders WTC cohort meets criteria for frailty, an association that increases with age, WTC exposure, and by occupation type (e.g. higher risk among construction worker). These findings underscore the need for routine systematic assessments of structured age-related indicators in the cohort. Therefore the overarching aim of this study is to assess whether previous WTC exposure leads to premature age-related deterioration in physiological function. We will develop a WTC- specific clinical frailty index based on clinically observable signs and symptoms of aging regularly examined within WTCHP surveillance. We will carry out analyses using the repository of WTC general responders cohort health monitoring data that has been collected at the Mount Sinai Clinical Center of Excellence (CCE) since 2002. Additionally, we will recruit 500 individuals from the WTC general responders cohort who are followed at the Mount Sinai Clinical CCE to collect new measures of cognitive function, grip strength, weight loss, physical activity, exhaustion and walking speed, which will improve the accuracy of the WTC clinical frailty index. We will first establish a validated frailty cutoff for a WTC-specific Clinical-FI using newly collected measures of cognition, grip strength, walking speed, unintentional weight loss, physical activity, and exhaustion (Aim 1) .We will assess the influence of WTC exposure severity on the development of frailty in WTC responders (Aim 2) and the association of WTC exposure (and other potential risk factors) with frailty trajectories (Aim 3). In an exploratory Aim we will assess the influence of frailty on other age-related syndromes (functional decline and falls) and key consequences (hospitalizations). Identifying modifiable risk factors for premature aging has the potential to impact the entire WTCHP, which is an aging cohort and at higher risk for negative consequences. Our broader focus on aging and frailty serves as a paradigm shift in the WTCHP from exposure and trauma- related injury. Results of this study will be instrumental in improving the capacity of the WTCHP to monitor and care for aging responders through partnership with Geriatrics and Palliative Care programs, including the development of future intervention research on the effectiveness of specific multifactorial preventive programs.